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Depression Is More Than Serotonin. So What is it?

Research Has Gone Beyond the Serotonin Theory of Depression — So Should We.

Key Takeaways:
  • The serotonin theory of depression was developed in the 1960s, and was considered groundbreaking for providing one of the first physiological explanations for this prevalent condition.
  • The serotonin theory and the closely related monoamine hypothesis led to the development of modern antidepressants, like SSRIs, that target depression by altering neurotransmitter levels.
  • Up to 16% of people will be diagnosed with depression at least once in their life.
  • One-third of those diagnosed with depression do not respond to antidepressants, indicating that neurotransmitters aren’t the entire picture. 
  • New research suggests that serotonin levels may not be as closely related to depressive symptoms as previously thought.
  • Many people who do respond to antidepressants tolerate them poorly, due to their higher propensity for side effects, which include sexual dysfunction and insomnia.
  • Too narrow of a focus on antidepressants as the primary and only treatment for depression may miss other common contributing factors, like inflammation and poor gut health.
  • 3–4 weeks on an anti-inflammatory diet, probiotic supplements, and plenty of sleep is a safe and effective place to start for boosting your mood.

In the 1960s, a concept known as the “serotonin theory of depression” emerged that put the spotlight on pinpointing the underlying, physical cause of mental illness. Serotonin is a neurotransmitter (a natural chemical in the brain) that helps regulate mood and emotions, often associated with feelings of happiness and well-being. Thus serotonin theory introduced the novel concept that depression was a result of a chemical imbalance, which later led to the development of modern antidepressants. 

Though this idea was revolutionary in the field of mental health treatment at the time, an intriguing issue persists to this day — approximately one-third of depression sufferers remain refractory to these interventions. Along with new research that suggests serotonin concentrations in the brain don’t correlate with depression as much as we previously thought, this underserved population has prompted a reevaluation of the serotonin-centered framework that we use when treating depression.

Even though the majority of clinical practice still revolves around serotonin theory, there is ample new research that shows that there are other factors at play that help drive depressive symptoms. Neuroinflammation (inflammation in the brain) is a top contender, and is especially important to consider for people who have exhausted conventional treatment options for depression.



Neuroinflammation is often a product of chronic disease and/or an unhealthy digestive system. Quelling a chronically overreacted immune response in the GI tract with an elimination diet, an anti-inflammatory lifestyle, and probiotic supplements has emerged as a viable treatment option for those struggling with low mood, and is a much-needed option for those who haven’t gotten relief with antidepressant therapy. 

Even better, these holistic treatments can avoid the unpleasant side effects of medication while addressing the underlying cause of depression. Let’s take a look at what has led to the development of the serotonin theory of depression, and see what cracks can be filled to help improve patient outcomes and create a more holistic approach to treating depression.

A Historical Recap of the Serotonin Theory of Depression

The 1960s brought forth the serotonin theory of depression, which began to shift the narrative around this pervasive, yet poorly understood, condition. At the time, depression was seen as a distinctly psychological (not physiological) phenomenon in the medical community. Because of this, there was a severe lack of treatments, which were limited to rest, electroconvulsive “shock” therapy, and medications that were largely ineffective with a high side effect profile.

It also heavily contributed to the negative stigma around this pervasive condition — around 14–16% of all people are suspected to experience depression at some point in their life, and major depressive disorder (MDD) is the most common mood disorder in the US [1, 2]. 

After its creation, the widespread dissemination of serotonin theory throughout the scientific community was groundbreaking for its novel and physiological explanation for depression. It purported that low levels of serotonin — one of our “feel good” neurotransmitters — in the brain were responsible for depressive symptoms. This debilitating, chronic condition was no longer “all in our heads” and now had an underlying physical component. 

It also suggested that this imbalance could be easily corrected by pharmaceuticals, which kicked-off much-needed developments in treatments for depression. Destigmatizing mental health still had a long way to go, but serotonin theory brought more awareness to depression and ultimately led to the creation of serotonin-based antidepressant drugs in the 1990s. 

To this day, researchers and clinicians rely heavily on serotonin theory and the closely related “monoamine hypothesis” — which accounts for imbalances of other neurotransmitters like dopamine and norepinephrine — for treating major depression. 

But, as we will see in a moment, the well-intentioned serotonin hypothesis might now be obscuring the most up-to-date research on depression that has far surpassed a chemical imbalance theory.

The Birth of SSRIs

Selective serotonin reuptake inhibitors (SSRIs) were the aptly named antidepressants that were created as a result of the serotonin hypothesis of depression, and are the most commonly prescribed antidepressant medication. Fluxotene was the first SSRI developed and released for use, but since then a number of other SSRIs have made their way to the market [3]:

  • Fluoxetine (Prozac)
  • Sertraline (Zoloft)
  • Paroxetine (Paxil)
  • Fluvoxamine (Luvox)
  • Citalopram (Celexa)
  • Escitalopram (Lexapro)

Prior to SSRIs, there were only a few medications for depression, including monoamine oxidase (MAO) inhibitors, and they came with serious potential side effects like hypertension and even death [1]. While MAOIs are still used to this day with a better understanding of how to prevent these issues, SSRIs are now widely preferred. 

SSRIs work by altering the amount of serotonin receptors on neurons to increase the amount of serotonin activity in the brain. They also help correct abnormalities of the serotonin transporter, SERT, which is another part of the serotonin system. 

They are more likely to be effective in treating moderate to severe cases of major depressive disorder, but are often unhelpful for mild depression [4]. Nonetheless, they are considered to be the first-line treatment for depression and are the most commonly prescribed antidepressants in psychiatry.

The Major Concern of Antidepressants — Side Effects

While SSRIs are tolerated better than other antidepressants for most people, they still come with their fair share of side effects, which may include [3]:

  • Sexual dysfunction
  • Sleep disturbances
  • Weight gain or weight loss
  • Digestive distress, including diarrhea
  • Nausea
  • Anxiety
  • Arrhythmia
  • Increased depressive symptoms
  • Dizziness
  • Dry mouth
  • Headache

One of the more commonly known risks of taking SSRIs is developing serotonin syndrome, which presents as high blood pressure, elevated heart rate, loss of coordination, confusion, insomnia, and agitation [3]. While this is unlikely to happen just from taking SSRIs, it can occur when they are taken alongside other medications (like MAOIs) or high doses of supplements that increase serotonin levels, like 5-HTP.

Unfortunately, side effects with any antidepressant are high, which is why many people prefer more natural methods, which I will get into later on. 

A 2018 meta-analysis evaluated 432 randomized controlled trials (RCTs) with over 100,000 participants to rank the efficacy of antidepressants for treating MDD in adults. The researchers found that all antidepressants slightly outperformed placebo in improving depressive symptoms to various degrees. For every 100 depressed adults who benefitted from placebo, 137 to 213 benefitted from antidepressants [5].

However, only two were well-tolerated, meaning that even those who benefit from antidepressants will likely deal with unwanted side effects. While fluoxetine was one of the two that made the cut for tolerability, it was one of the lowest in efficacy for treating depression. 

Side Effects Can Lead to Research Bias

Side effects aside, one of the biggest issues that you can run into from taking antidepressants is them simply not working, and there is quite a bit of controversy surrounding the reliability of antidepressant research.

One of the main problems researchers run into with antidepressant clinical trials is that they may suffer from unblinding bias. When a study participant takes a drug with obvious side effects (often the case with antidepressants), they are likely to realize they were not given a placebo and then overestimate the effects of the drug. The results of such studies may therefore be unreliable or misleading when they suggest a drug is better than a placebo [6].

Researchers have caught on and recent study methodologies have adjusted for the unblinding bias. A high-quality analysis found that SSRIs are significantly effective in treating depressive symptoms, even when side effects were not present [7]. However, bias is still rampant in antidepressant research, and most study results in this field have to be interpreted with caution.

This is part of the reason why study findings in antidepressant research can be conflicting. Ultimately, when considering the literature as a whole, it seems that some people respond well to antidepressants, but many do not. There is a significant need for treatment options that aren’t based solely on altering serotonin and other neurotransmitter levels.

The Burden of Treatment-Resistant Depression

A large portion of patients, estimated to be around 30%, are treatment-resistant for depression, meaning that they failed to improve with at least two separate antidepressants at various strengths, and their estimated quality of life can be up to 40% lower than those who respond to depression treatments [8, 9]. When considering all psychiatric disorders, the number of treatment-resistant individuals jumps to 60% [9]. 

Treatment in these populations often falls back on using higher doses of antidepressants, multiple antidepressants at once, and/or prescribing last-resort pharmaceuticals like clozapine. As you can imagine, this creates a significantly higher likelihood for side effects and is essentially throwing more of what already doesn’t work in these populations. 

Ketamine is becoming more popular for treatment-resistant, severe MDD, and has seen great success in the research [10]. However, treatment must be administered under doctor supervision, is expensive, has a high propensity for side effects and abuse, and its antidepressant effects only last a few weeks in most people. It can be a life-saving treatment for some, but at the end of the day, it’s just not accessible for most people.

It’s clear from how many people continue to live with depression after trying antidepressants that neurotransmitters are just one part of the picture when it comes to treating depression. Maintaining too narrow of a focus in this area may be causing us more harm than benefit in modern-day practice.

Serotonin Isn’t the Whole Picture

Serotonin imbalances in mental health conditions are widely known, even among patients, and surveys suggest that about 80% of the general public believes that some type of neurotransmitter imbalance is responsible for depression (11). As a quick search on the internet will show, depression has become nearly inseparable from the terms “neurotransmitters”, “serotonin”, and “dopamine”.

However, the research shows that mental illness isn’t easily reduced to being an excess or deficiency of specific neurotransmitters. While alterations in the production and uptake of these chemicals are undoubtedly involved in the development of depressive symptoms and MDD, it isn’t the entire picture for most people.

New Research Sheds Light on Serotonin Theory

A 2022 systematic umbrella review of the evidence reviewed the most up-to-date findings in the literature to see if they support the serotonin theory of depression. As I reviewed on Dr. Ruscio Radio, Moncrieff et al. found that there was no association between levels of serotonin in cerebrospinal fluid (CSF) and depression [11].

Prior neuroscience research has attempted to gain clarity on the link between plasma serotonin levels and depression but has received valid criticism as serotonin levels in the blood are a poor indicator of levels in the brain (where it matters the most when it comes to depression). However, CSF circulates throughout the central nervous system and is a more reliable indicator of what neurotransmitter levels actually look like in the brain.

The review found evidence that serotonin binding, a function of SSRIs, was inconsistently and weakly linked with depression, and there was no association between serotonin-related genes and depression [11]. Tryptophan depletion — an amino acid precursor to serotonin — was not found to lead to depressive symptoms.

In summary, some of the highest-quality evidence we have to date shows that serotonin theory is no longer the only (or preferred) explanation for depression. Being overly dogmatic in clinical practice with how we choose to treat depression runs the risk of limiting the number of treatments available to us.

All things above considered, it appears that there’s a time and place for pharmaceutical antidepressants for some people, but they don’t work for everyone. Relying solely on these medications can miss many underlying causes of depression, lead to unwanted side effects, and/or simply not improve depressive symptoms.

Where Does Depression Treatment Go From Here?

With light being shed on the limitations of our most common treatments for depression, it’s easy to become discouraged. Thankfully, current depression research has far surpassed serotonin therapy tunnel vision. Challenging the belief that depression is solely due to our chemical makeup has proven to be a good thing for advancements in mental health treatment.

These findings mean that we are no longer just a product of our genes. Even if you have a family member who deals with depression or you have a known genetic mutation in a serotonin gene, you are not reduced to simply that. As we can see above, our genes are not always a reliable predictor of who will and will not experience depression and are just one part of the story. 

Turns out that through epigenetics, we can positively influence our genes by choosing to live a healthy lifestyle. A nutrition-packed, anti-inflammatory diet, regular exercise, and quality sleep have far more influence on depression than a single genetic mutation. Knowing that we are far more than our genetics helps to empower us to take matters into our own hands.

Finally, as discussed above, the vast quantity of people with depression and/or other mental health concerns who do not respond to pharmaceuticals is staggering. This research gives hope to those who fail to respond to the use of antidepressants, and suggests that there is more to treating depression than simply serotonin or any other single factor. 

Pushing outside the limits of serotonin theory reminds us to stay humble, remain willing to question current practices, and keep a mindset of “evidence-based” but not “evidence-limited”. 

Curbing Inflammation is a Powerful “Antidepressant”

Though neurotransmitters like serotonin are clearly an important part of the picture when it comes to depression, the sheer amount of people who do not benefit means there must be something else at play. 

New research has shed light on these underlying factors, and it seems that chronic inflammation is extremely influential. People with depression have been shown to have higher levels of inflammation, compared to non-depressed populations [12, 13], and it is significantly higher in those with a history of self-harm [14]. 

It’s important to pause here and note that this does not mean that inflammation directly causes depression. It’s just as likely that depression leads to inflammation, or even that another underlying factor may be responsible for both the inflammatory response and depressive symptoms. However, the link between the two is strong, and several literature reviews have shown that depression regularly occurs with chronic inflammatory illnesses, such as IBD, cancer, or heart disease [15, 16]. 

Notably, people who do not respond to antidepressants have higher levels of inflammation [17], meaning that lowering inflammation levels can be especially helpful in people who are treatment-resistant. Interestingly, people who do respond to antidepressants have lower inflammation after starting their medication, and Prozac (the original SSRI) has actually been shown to reduce inflammation levels [18, 19]. 

It begs the question, are SSRIs effective because of their effects on low serotonin levels, or because they adeptly suppress inflammation? While this doesn’t technically matter in those who do respond well to antidepressants, this speculation opens up a new world of treatment options for those who don’t. 

A Holistic Approach to Depression Treatment

While both factors undoubtedly play a role, research suggests that targeting inflammation is just as important (if not more) than serotonin levels for treating depression. 

An anti-inflammatory lifestyle is essential for reducing symptoms of depression and significantly broadens the treatment options for depression. The following can effectively lessen the symptoms of depression, and while they are powerful tools for improving mental health, their benefits are body-wide.

  • Quality sleep: Sleep is essential, and consistently getting 7 hours of sleep or less is associated with high markers of inflammation such as CRP. Just one night of sleep deprivation can increase inflammatory cytokines like IL-6 and TNF-α [20].
  • Physical activity: Research shows that exercise may be just as effective as antidepressants when it comes to mild to moderate depression. A meta-analysis of more than 2,500 participants found that there was no difference in benefits when comparing exercise to antidepressants [21]. 
  • Stress reduction: Nature may be our best natural antidepressant, as spending time outdoors evokes a positive affective response, which translates to being more alert, happy, and confident [22]. Five minutes of nature time per day is enough to positively impact your mood [23].

Many people simply prefer a more natural approach to treating their mental health, and I tend to take the approach of starting with more natural solutions that have been shown to be effective, before recommending medication (check with your provider first).

Importantly, adopting a healthy lifestyle is a safe treatment option for people who are already taking antidepressants and want to target any unresolved symptoms, or who want to decrease their dose of antidepressants due to side effects or not wanting to rely on medication. Of course, I can’t go without saying that if you are taking any type of antidepressant, it’s essential to work alongside your provider to determine if you are a good candidate for decreasing your dose or weaning off. 

Your Mood Starts With Your Gut

The vagus nerve connects the digestive tract and the central nervous system to each other to form a highway of bidirectional communication, known as the gut-brain axis. This connection is important for understanding how to best treat depression, as an unhealthy digestive tract can directly affect the brain. 

Inflammation in the gut and/or an imbalance in the gut microbiome can lead to depressive symptoms through two main mechanisms:

  1. Leaky gut: Inflammation in the intestinal tract can create intestinal permeability (leaky gut)  — where the connections between the epithelial cells lining the small intestine are weakened, allowing foreign particles to escape into the bloodstream. This creates an inflammatory process throughout the body, including the brain, known as neuroinflammation [24, 25].
  2. Vagus nerve dysfunction: Neurochemicals like serotonin and dopamine are made in the digestive tract and travel along the vagus nerve to the brain, where they influence mood [26, 27]. Inflammation in the gut can negatively affect vagus nerve function and disrupt the flow of these neurotransmitters to the brain. 

Disruptions to the gut flora can be especially influential on our mental health. There is a complex community of microorganisms living in our gut known as our gut microbiome that helps regulate our mood and overall health. When this community is imbalanced, known as dysbiosis, it can trigger neuroinflammation and lead to depressive symptoms [28, 29, 30, 31, 32].

People with depression may be more likely to have gut dysbiosis [33], and depression is a common symptom for people with digestive issues. A 2019 meta-analysis of 22,842 participants found that people with IBS are 3x more likely than healthy people to have depression, and symptoms of low mood are present in nearly 30% [34]. Other research suggests that this number might be closer to 50%, and that depression is one of the most commonly reported non-digestive symptoms in IBS patients [35, 36]. 

Depression is commonly found alongside other gut conditions like non-celiac gluten sensitivity (NCGS), and inflammatory bowel disease (IBD), further strengthening the link between poor gut health and low mood [34, 35, 36, 37, 38, 39, 40]. 

These research findings give us great insight on where to start when it comes to improving mental health, and/or when antidepressants have failed to give relief. Providing a healthy environment for your gut can be a game changer when it comes to lifting your mood.

How to Heal Your Digestive Tract

While I get into it in greater detail in my book, Healthy Gut, Healthy You, there are a few fundamentals that nearly all of my patients implement when healing their gut: an anti-inflammatory diet, probiotics, exercise, and quality sleep. 

An anti-inflammatory diet is one of the best places to start, as it can quell intestinal inflammation and balance your gut bacteria. I find that a temporary 3–4 week elimination diet that removes the common inflammatory triggers, like sugar, dairy, wheat, and corn is enough to reduce symptoms in most people. 

The Paleo diet helps to calm inflammation by minimizing your exposure to foods that provoke an immune response [41, 42], making it a straightforward place to start. However, there are certainly other elimination diets that may better suit your needs or in the event that your symptoms don’t fully respond to Paleo. I have a guide here that can help you determine what diet is right for you. 

Healthy Bacteria for a Healthy Mind

It’s hard to talk about gut health without mentioning probiotic supplements, as they are vital in reducing inflammation and balancing the biome. Probiotics help to:

  • Increase the bacterial diversity, or health, of your bacterial community [43, 44, 45]
  • Fight pathogens (harmful bugs) and their toxins [43, 44, 46, 47, 48]
  • Reduce gut inflammation and promote a healthy immune response in your gut [43, 44, 45, 49, 50, 51]
  • Reduce gut inflammation [43, 44, 45]
  • Reduce leaky gut, which is damage to your gut lining [43, 44, 52, 53, 54]

A 2023 meta-analysis of 20 RCTs examined how probiotics affect people with depression. While the effects on inflammation were mixed, compared to placebo, probiotics can relieve depression in depressed people with or without physical conditions [55]. This included people with IBS, constipation, history of heart attack, coronary artery disease, and kidney disease.

Another meta-analysis found that people who took probiotics, especially multiple strains, had a much greater reduction in depressive symptoms than those who took a placebo [56]. Other high-quality research supports that probiotics can lead to significant improvements in mood in depression populations [57, 58]. However, it’s still unclear whether probiotics can prevent depression in healthy people [55].

Different types of probiotics can offer health benefits, and it’s likely that no single strain is best when it comes to treating depression. Because of this, I prefer a “broad-spectrum” probiotic — one that contains many different species — that can give you maximum benefit. I have another article where I get more into the specifics of the different categories of probiotics, and if you’re ready to give them a shot, you can find our Triple Therapy Probiotic Sticks in our online store

Combined with the lifestyle recommendations mentioned above, a healthy diet and introducing good bacteria are a great place to start when treating your depression naturally. 

Say “So Long” to the Serotonin Theory of Depression 

Depression research has outgrown the serotonin hypothesis of the 1960s. While many people benefit from the medications that came from this theory, there are millions of people who don’t respond to these drugs. Fortunately, recent research into this topic highlights that there may be other mechanisms to depression, aside from just neurotransmitters, primarily inflammation.

Through the use of an anti-inflammatory diet and probiotics, and living a healthy lifestyle, you can significantly improve your mood naturally and have minimal-to-no side effects. Reach out to the Ruscio Institute for Functional Health for help with treating depression holistically and naturally. 

The Ruscio Institute has developed a range of high-quality formulations to help our patients and audience. If you’re interested in learning more about these products, please click here. Note that there are many other options available, and we encourage you to research which products may be right for you.

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